DJ1 Function

Early evidence suggested the involvement of DJ-1 in cell-cycle regulation and oncogenesis, sperm maturation and fertilization, control of gene transcription, regulation of mRNA stability, and response to cell stress. Initially, a human cDNA termed DJ-1 was identified as a novel oncogene that transformed NIH3T3 cells in cooperation with H-Ras (24). More recent proteomic-based studies found increased expression of the DJ-1 protein in various human tumors, confirming the involvement of DJ-1 in...

Mutation Analysis

Several studies have now been carried out to evaluate the PINK1 mutation burden in PD patients around the world. These data demonstrate that PINK1 mutations account for 5 to 10 of ARPD cases. The emerging phenotype is of early-onset PD (range 18-39 years) lacking major atypical features. This suggests that PINK1 is distinct from parkinsonism associated with PARKIN or DJ-1. While PINK1 is unequivocally associated with young-onset ARPD, it remains difficult to quantify the overall proportion of...

Levodopa Therapy For Parkinsons Disease Historical Introduction

Following the discovery of striatal dopamine deficiency in PD (36,37), Birkmayer and Hornykiewicz (38) injected small doses of levodopa (up to 150 mg) intravenously and reported a transient reversal of akinesia. Levodopa was previously shown by Carlsson et al. (39) to reverse reserpine-induced parkinsonism in rabbits. Barbeau et al. (40) also reported benefit with small oral doses of levodopa (200 mg). Subsequently, many other investigators using small oral or intravenous doses reported similar...

Identification Of Park7idj1

The PARK7 locus was identified as part of a research program Genetic Research in Isolated Populations (GRIP) (17). This study population from the southwest of the Netherlands has been genetically isolated for several centuries. Since 1750, this population has grown with minimal immigration from 150 individuals to an estimated 20,000 descendants, now scattered over eight adjacent villages, suggesting that the genetic background of this population could be more homogeneous than that of the...

Genetics of Parkinsons Disease

Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland, U.S.A. Alzheimer's Laboratory, Sant Pau Hospital, Barcelona, Spain HEREDITY AND GENETICS IN PARKINSON'S DISEASE Eighty years after James Parkinson wrote his Essay On the Shaking Palsy, Gowers (1) suggested that genetics may play a substantial role in Parkinson's disease (PD), a view shared by Charcot's student Leroux, who stated, A true cause of paralysis agitans, and perhaps the only...

Pink1 And Mitochondrial Dysfunction

Mitochondrial dysfunction has long been associated with PD. Respiratory chain enzyme deficiencies have been widely reported in the substantia nigra of sporadic PD patients (20-22). Complex I is vulnerable to modification by oxidative stress, and when deregulated is a source of free radicals or reactive oxygen species (ROS) (23,24). Mitochondria are the main providers of cellular energy, sustaining aerobic life through the flow of electrons down the electron transport system (ETS). The ETS is...

Applications of the Drosophila aSynuclein Model

The coincidence of neuronal loss and the formation of a-synuclein positive aggregates in a-synuclein-expressing flies prompted several studies of the possible involvement of aggregate formation in dopamine neuron loss. The first study in Drosophila to investigate this matter demonstrated that overexpression of the chaperone, HSP70, abrogated the a-synuclein-induced loss of TH-positive neurons without detectably influencing the appearance of Lewy body-like aggregates (42). Furthermore, feeding...

THE aSynuclein Transgenic Drosophila Model Of Parkinsons Disease Generation and Characterization

The first gene shown to be associated with a heritable form of PD, a-synuclein, was also the first of the PD-related genes to be studied in Drosophila. Although mutations of the a-synuclein gene appear to be an extremely rare cause of PD, the finding that a-synuclein is a component of the Lewy body protein inclusions observed in patients with the sporadic form of the disease implies that this factor is a causative agent in most forms of PD (36,37). Thus, insight gleaned from studies aimed at...

References

In Olanow CW, Lieberman AN, eds. The Scientific Basis for the Treatment of Parkinson's Disease. Carnforth, England Parthenon Publishing Group, 1992 89-112. 2. Quinn N, Critchley P, Marsden CD. Young onset Parkinson's disease. Mov Disord 1987 2 73-91. 3. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease. Neurology 1991 41 202-205. 4. Quinn NP. A case...

Genomic Organization Of The Tau Gene Gene Structure and Splicing

MAPT is located in chromosome 17q21 and consists of a noncoding exon 0 followed by 14 coding or partially coding exons (Fig. 1A) (30). Intron 13 is always retained in human MAPT transcripts, resulting in a single last exon comprising exon 13, intron 13, exon 14, and containing the 3' untranslated region (3'UTR). Restriction analyses showed that MAPT contains two CpG islands, one associated with the promoter region upstream of exon 0, the other with exon 9 (31). MAPT produces three FIGURE 1 (A)...

Analytical Epidemiology

The study of PD presents special challenges for risk-factor assessment. There is likely a long period of time when neurons are already damaged, but symptoms are not yet apparent. The length of this silent period may vary among individuals. For this reason, it is difficult to estimate the optimal time frame for queries about past exposures. Risk Factors for Parkinson's Disease Interest and results in the search for environmental risk factors associated with the development of PD have increased...

Phosphorylation and Glycosylation

Phosphorylation is a common mechanism for regulating the activity and function of proteins. In AD, phosphorylation of the cytoskeletal protein tau is associated with disease (102), and it is reasonable to suspect that a similar mechanism may be involved with a-synuclein in PD. In vitro, it has been shown that a-synuclein can be phosphorylated at serine 129. In transfected cells, this phosphorylation is insensitive to stimulation of PKC and protein kinase A (PKA), and at steady state the...

Functional Analysis of a Drosophila PINK1 Ortholog

Three recent papers described the effects of perturbation of a Drosophila homolog of the PINK1 gene (79-81). The human PINK1 gene encodes a putative protein kinase that is upregulated in cancer cells by the tumor-suppressor PTEN (82). The presence of a putative mitochondrial targeting sequence in PINK1 coupled with its predominant localization to mitochondria (83,84) strongly suggested that loss-of-function mutations in PINK1 somehow compromise mitochondrial integrity. This prediction is born...

Mutations In Mapt Overview

In 1994, it was demonstrated that the Irish Mo family, presenting with a disorder then referred to as complex (DDPAC), was genetically linked to a region in chromosome 17q21 including MAPT (55). Individual Mo family members presented with a variety of clinical phenotypes, but the combination of FTD and parkinsonism was most commonly observed. The next two years, follow-up linkage studies in families with autosomal dominantly inherited forms of FTD collected from around the world, established...

Levodopa in Patients with a History of Melanoma

Levodopa is an intermediary metabolite in the synthesis of melanin. For this reason, there has been long-standing concern that this medication might potentially promote the growth of melanoma. While melanoma obviously occurs in patients on levodopa therapy, there is no evidence that the incidence differs from that in the general population (96-99), other than that there seems to be a higher risk for melanoma in patients with PD, even without levodopa treatment (100). In studies of patients with...

The Synuclein Protein Family Structure

A-Synuclein is a small, synaptically localized protein that is expressed most abundantly in neurons (10,11). a-Synuclein, which has been mapped to chromosome 4q21 (12), is the major component of pathological inclusions in PD and other a-synucleinopathies (1,13), and mutations in a-synuclein (A53T, A30P, and E46K) or duplications of this gene have been linked to familial forms of PD and DLB (3-5,14). Studies of the toxicity and pathogenesis of a-synuclein have focused on the polymerization of...

Is Levodopa Neurotoxic or Neuroprotective

One of the most controversial questions regarding the treatment of PD is whether levodopa is neurotoxic. The results of many in vitro studies have suggested that levodopa may be injurious to dopaminergic neurons (86,87). These findings have raised concerns that chronic levodopa exposure might hasten disease progression in PD patients. Accordingly, some physicians and patients have opted to defer the use of levodopa for as long as possible (28). Other physicians have continued to use levodopa as...

Matrix

FIGURE 1 Schematic diagram of the mitochondrial ETC. Note the site of complex I inhibition by rotenone and MPP+, electron leakage and ROS production. Abbreviations ADP, adenosine diphosphate ATP, adenosine triphosphate ETC, electron transport chain FAD, flavin adenine dinucleotide FADH2, flavin adenine dinucleotide MPP, 1-methyl-4-phenyl-2,3-dihydropyridinium ion NADH, nico-tinamide dinucleotide ROS, reactive oxygen species TCA, trycarboxylic acid. FIGURE 1 Schematic diagram of the...

Sonic Hedgehog Agonists

The hedgehog family is composed of signaling molecules, including sonic hedgehog is associated with patterning during CNS development. There is also evidence that it promotes survival of dopaminergic neurons, protecting cultures of fetal mid-brain dopaminergic neurons from MPP(+). In the adult brain, Bezard et al. showed that sonic hedgehog is reduced in Parkinson's disease, and its injection inhibits electrical activity in the subthalamic nucleus. (37). Tsuboi and Shults, studying parkinsonian...

Transgenic Mice Using Cell Type Specific Promoters

In addition to using promoters that drive expression of transgenes in a wide variety of neuronal populations, a number of transgenic lines expressing human a-Syn variants using a neuronal cell type specific promoter. Thus far, transgenic mice expressing a-Syn in DAergic neurons and in oligodendrocytes have been reported. First of these mice used a 4.8 kb rat tyrosine hydroxylase (TH) promoter was used to drive high levels of wild type and mutant (A30P and A53T) Hua-Syn expression in DAergic...

Phenotype Of Parkinrelated Parkinsons Disease Clinical Features

The most typical features of Parkinson's disease caused by PARKIN mutations are early-onset typical parkinsonism with a slow clinical course, good or excellent response to low doses of levodopa, frequent treatment-induced dyskinesias and the absence of dementia (47,99). Other frequent signs, that occur in less than 50 of the cases, however, are foot dystonia, brisk reflexes, sleep benefit, and psychiatric or behavioral disorders (Table 1). Two studies (47,90) have compared the frequency of...

Lrrk2 Genetics From Rare Cause To Common Association

The large family from Sagamihara suggested that the PARK8 locus was probably a rare cause of atypical parkinsonism, without the typical Lewy pathology found in sporadic PD (see below). However, groups in other parts of the world were able to find evidence of linkage to the same chromosomal region (8,9), indicating that one gene was likely to be responsible for autosomal dominant disease in several families. The cloning of LRRK2 revealed that there are indeed multiple variants associated with...

Astrocyte Modulation

The calcium binding protein S100B may promote neuronal damage by the activation of various intracellular signaling pathways. Astrocytic activation may increase the production of S100B in the MPTP models of PD, thereby potentiating the neurodegeneration. Arundic acid R - - -2-propyloctanoic acid ONO-2506 is an agent that inhibits S100B synthesis in cultured astrocytes, which has also been shown to reduce delayed ischemic brain damage in models of cerebral ischemia. In an MPTP model of PD, Kato...